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WO2006131757A1 - Procede et compose - Google Patents

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Publication number
WO2006131757A1
WO2006131757A1 PCT/GB2006/002140 GB2006002140W WO2006131757A1 WO 2006131757 A1 WO2006131757 A1 WO 2006131757A1 GB 2006002140 W GB2006002140 W GB 2006002140W WO 2006131757 A1 WO2006131757 A1 WO 2006131757A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxy
isobutyl
protected
nitrobenzene
methanol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2006/002140
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English (en)
Inventor
Noel Hamil
Georges Hodges
Ian Houson
Susan Pollard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NPIL Pharmaceuticals UK Ltd
Original Assignee
NPIL Pharmaceuticals UK Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NPIL Pharmaceuticals UK Ltd filed Critical NPIL Pharmaceuticals UK Ltd
Priority to US11/917,090 priority Critical patent/US20080200724A1/en
Priority to JP2008515294A priority patent/JP2009502741A/ja
Priority to CA002608511A priority patent/CA2608511A1/fr
Priority to EP06744186A priority patent/EP1893565A1/fr
Publication of WO2006131757A1 publication Critical patent/WO2006131757A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This invention relates to a process for preparing certain sulphonamide intermediates useful in the preparation of HIV inhibitors, and to the crystal forms thereof.
  • HAV Human immunodeficiency virus
  • AIDS the causative agent of acquired immunodeficiency syndrome
  • HfV protease encodes three enzymes, including the well- characterized proteinase belonging to the aspartic proteinase family, the HfV protease. Inhibition of this enzyme has been regarded as a promising approach for treating AIDS. Hydroxyethylamine isosteres have been extensively utilized in the synthesis of potent and selective HIV protease inhibitors. However, this modern generation of HiV protease inhibitors has created an interesting challenge for the synthetic organic chemist. Advanced x-ray structural analysis has allowed for the design of molecules that fit closely into active sites on enzymes creating very effective drug molecules.
  • HIV inhibitors designed by molecular shape, are often difficult to produce using conventional chemistry.
  • the modern generation of HIV inhibitors has structural similarities in a central three-carbon piece containing two chiral carbons that link two larger groups on each side (see, e.g., Parkes, et al, J. Org. Chem., 39:3656 (1994)).
  • the chemical bond from the central part to one of the larger groups is a carbon-nitrogen bond which is usually accomplished by reacting an epoxide with an amine.
  • 2R,3S-N-isobutyl-N-(2-hydroxy-3- amino-4-phenylbutyl)-p,-nitrobenzenesulfonylamide hydrochloride is a key intermediate in the synthesis of protease inhibitors (see, e.g., US5,585,397, US5, 723,490 and US5,783,701 and WO94/0563).
  • protease inhibitors see, e.g., US5,585,397, US5, 723,490 and US5,783,701 and WO94/0563.
  • Scheme 1 One process currently used to prepare 2R,3S-N-isobutyl- N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride is illustrated Scheme 1.
  • the 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene- sulfonylamide hydrochloride may be made in 4-step process starting from a commercially available (Aerojet Fine Chemicals (Sacramento, Calif.)) starting material, 2S.3S- chloromethylalcohoi (2S.3S-CMA).
  • 2R,3S-N- ⁇ sobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitro- benzenesulfonylamide hydrochloride may be made according to an improved process described in US6548706 which avoids the need to prepare and isolate the epoxide. This improved process is claimed to result in higher yields of 2R,3S-N-isobutyl-N-(2-hydroxy-3- amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride,- while not sacrificing its purity.
  • a process for preparing a BOC-protected 2R,3S-N-isobutyi-N-(2-hydroxy-3-amino-4-phenyIbutyl)-p- nitrobenzene-suifonylamide wherein the BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3- amino-4-phenylbutyl)-p-nitrobenzene-sulfonyiamide is isolated from a solution comprising methanol and BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy ⁇ 3-amino-4-phenylbutyl)-p- nitrobenzene-sulfonylamide.
  • the solution comprising methanol and BOC-protected 2R,3S-N-isobutyl-N-(2- hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene-sulfonylamide includes solutions wherein the BOC-protected 2R,3S-N-lsobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p- nitrobenzene-sulfonylamide is fully dissolved in methanol or methanol containing solvent mixtures, and solutions wherein the BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3- amino-4-phenylbutyl)-p-nitrobenzene-sulfonylamide is partially dissolved in methanol or methanol containing solvent mixtures, for example slurries of BOC-protected 2R,3S-N- isobutyl-N-(2-hydroxy-3-amin
  • the solution comprising methanol and BOC-protected 2R,3S-N-isobutyl-N-(2- hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene-su!fonylamide may be obtained by dissolving BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p- nitrobenzene-sulfonylamide in methanol or methanol containing solvent mixtures, or by slurrying BOC-protected 2R,3S ⁇ N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p- nitrobenzene-suifonylamide in methanol or methanol containing solvent mixtures.
  • the solution comprising methanol and BOC-protected 2R,3S-N-isobutyl-N- (2-hydroxy ⁇ 3-amino-4-pheny!buty!-p-nitrobenzene-sulfonylamide may be obtained by direct addition of methanol to a solution comprising BOC-protected 2R,3S-N-isobutyl-N-(2- hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene-sulfonylamide or by solvent exchange, whereby the solution solvent is exchanged for methanol or a methanol containing solvent mixture, or by synthesing BOC-protected 2R,3S-N-isobutyl-N ⁇ (2 ⁇ hydroxy-3-amino-4- phenylbutyl)-p-nitrobenzene-su!fonylamide in methanol or a methanol containing solvent mixture.
  • Methanol containing solvent mixtures include any solvent mixtures comprising methanol in which the BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4- phenylbutyl)-p-nitrobenze ⁇ e-sulfony!amide can be solubilised.
  • the solvent mixtures comprise organic solvents which are miscible with methanol.
  • Preferred organic solvents include alkyl acetates, for example, methyl acetate, ethyl acetate, propyl acetate, for example isopropyl acetate, butyl actetate, for example isobutyl acetate or t-butyl acetate, and aromatic solvents, for example, toluene, benzene and xylene, and mixtures thereof.
  • alkyl acetates for example, methyl acetate, ethyl acetate, propyl acetate, for example isopropyl acetate, butyl actetate, for example isobutyl acetate or t-butyl acetate
  • aromatic solvents for example, toluene, benzene and xylene, and mixtures thereof.
  • Highly preferred methanol containing solvent mixtures include methanol/toluene mixtures, methanol/ethyl acetate mixtures and methanol/toluene/ethyl acetate mixtures.
  • the methanol content is greater than 10%, more preferably greater than 30% and most preferably greater than 40% by volume with respect to the total volume of solvents present.
  • the other non-methanol solvents are preferably present in ratios ranging from 1:99 to 99:1, more preferably in ratios ranging from 25:75 to 75:25, and most preferably in ratios ranging from 60:4Q to 40:60, for example 50:50.
  • the BOC-protected 2R,3S-N-isobutyi-N-(2-hydroxy-3-amino-4- phenylbutyl)-p-nitrobenzene-sulfony!amide is isolated by crystallisation or by precipitation techniques, for example by addition of an antisolvent.
  • 3-amino-4-phenyibutyl)-p-nitrobenzene-sulfonylamide is dissolved by heating in methanol or a methanol comprising solvent mixture to form a saturated or partially saturated methanol containing solution.
  • the saturated or partially saturated methanol containing solution is filtered to remove any insoluble material, then the saturated or partially saturated methanol containing solution is cooled to precipitate the BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene-sulfonylamide.
  • methanol is added to a heated saturated or partially saturated solution of BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy ⁇ 3-amino-4- phenylbutyl)-p-nitrobenzene-sulfonylamide in a non-methanol solvent or solvent mixture, for example toluene, ethyl actetate or toluene/ethyl " acetate mixture.
  • a non-methanol solvent or solvent mixture for example toluene, ethyl actetate or toluene/ethyl " acetate mixture.
  • saturated or partially saturated methanol containing solution is filtered to remove any insoluble material, then the saturated or partially saturated methanol containing solution is cooled to precipitate the BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4- phenylbutyl)-p-nitrobenzene-sulfonylamide.
  • saturated or partially saturated methanol containing solution refers to solutions at a reference temperature which comprise concentrations of dissolved solids, the concentration having an upper value defined by the maximum concentration achievable at the reference temperature and having a lower limit defined by the maximum concentration achievable at lower, end-point, temperature.
  • solutions having concentrations of dissolved solid between the upper and lower values at the reference temperature will result in precipitation of the dissolved solid when cooled to the lower, end-point temperature.
  • the upper and lower concentration values are therefore dependent on the solubility characteristics of the materia! and the solvent mixture of choice.
  • solvent mixtures comprising methanol and one or more of toluene or ethyl acetate
  • the maximum solubility achievable at 6O 0 C is 24%w/w
  • the lower, solubility value, for an end-point temperature of O 0 C is typically 0.3%w/w.
  • the concentration of BOC- protected 2R,3S-N-isobutyl-N- ⁇ 2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene- sulfonylamide is in the range from 0.3 to 24%w/w.
  • saturated or partially saturated methanol containing solution is cooled to precipitate the BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p- nitrobenzene-sulfonylamide, it is preferred that saturated or partially saturated methanol containing solution is initially heated to over 40 0 C, more preferably to over 50 0 C and most preferably to at least 65°C.
  • Cooling is preferably carried out slowly, whereby cooling is sufficiently slow to avoid secondary nucleation.
  • cooling is carried out under ramping conditions as known in the art. More preferably, ramped cooling conditions start with a slow cooling rate and the cooling rate is gradually increased as time elapses.
  • the cooling rate may be increased by a simple gradient increase or by multi-gradient increases, for example exponential increases.
  • a saturated or partially saturated methanol containing solution at an initial elevated temperature preferably of from, 45 0 C to 75°C is cooled stepwise, whereby the saturated or partially saturated methanol containing solution is cooled at a first cooling rate until a first temperature is reached, optionally the solution is held at this first temperature, preferably for 1h or more, then cooling is recommenced at a second cooling rate until a second temperature is reached.
  • the solution is held at this second temperature, preferably for 1h or more, and optionally cooled further in one or more steps.
  • the second cooling rate is slower than any subsequent cooling rates.
  • the first cooling rate is less than 30°C/h and the first temperature is from 44°C to 50 0 C.
  • the second cooling rate is less than 10°C/h, more preferably less than 4°C/h, and the second temperature is from 34 0 C to 36 0 C.
  • Subsequent cooling is preferably carried out at rates from 5°C/h to 30°C/h, more preferably between 5°C/h to 10°C/h.
  • the final temperature is from 0 0 C to minus 1O 0 C.
  • the methanol containing solution is preferably held at 0 0 C for up to 1hr before recovering the crystalline BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino- 4-pheny!butyl)-p-nitrobenzene-sulfony!amide.
  • Faster and slower cooling rates may be employed. While increased cooling rates may be accompanied by some deterioration of the physical form, slower cooling rates appear not to be detrimental to the physical form.
  • Preferred ripening processes include heating suspended BOC-protected 2R.3S-N- isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene-sulfonylamide in methanol or a methanol containing solvent mixture at an elevated temperature, preferably from 25 0 C to 45 0 C, for a period of time before slowly cooling to O 0 C.
  • the period of time is chosen to allow sufficient time for the physical form to change.
  • Ripening processes may however prove time consuming, thus whiie the effects of over fast cooling may be ameliorated, additional time consuming steps may render the process less economical.
  • the saturated or partially saturated methanol containing solution is seeded with crystalline BOC-protected 2R,3S-N ⁇ isobutyi-N-(2-hydroxy-3-amino-4-phenyibutyi)- ⁇ - nitrobenzene-sulfonylamide.
  • the quantity of seed crystal employed may be determined by methods known in the art.
  • the point of seeding can be derived from the solubility curve and by determining the point of turbidity change. When small quantities of seed are added while supersaturating the solution, the point of seeding is reached when turbidity increases on seeding.
  • a crystalline BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene- sulfonylamide obtainable by the processes of the first aspect of the present invention.
  • BOC-protected 2R,3S-N-isobutyl-N-(2- hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene-sulfonylamide is polymorphic. • By using the processes of the present invention certain crystal forms can be obtained.
  • Crystal Form I When methanol is used as the sole solvent, a crystalline BOC-protected 2R,3S-N- isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene-sulfonylamide of Crystal Form I is obtained.
  • the habit of Crystal Form I is prismatic and thus is amenable to easy filtration.
  • Crystal Form I When measured by X-ray diffraction (Siemens D5000 X-Ray Diffractometer, 2 ⁇ , CuKa radiation) Crystal Form I shows strong peaks at 3.9 and 8.2, moderate peaks at 9.3, 13.7 18.7, 19.0 and 19.5 and weak peaks at 7.5, 7.8, 11.7, 12.1 , 15.1 , 15.6, 16.5, 17.2, 17.6, 20.0, 20.8, 21.8, 22.7, 23.4, 24.5, 27.4 and 28.4.
  • Crystal Form Il When measured by X-ray diffraction (Siemens D5000 X-Ray Diffractometer, 2 ⁇ , CuK ⁇ radiation) Crystal Form Il shows strong peaks, at 5.3 and 8.3, moderate peaks at 6.7, 10.7, 13.4, 18.8, 19.6, 21.3 and 23.8 and weak peaks at 7.9, 17.3, 20.6 and 21.9.
  • Crystal Form III when no methanol is present and only ethyl acetate is used as the sole solvent, Crystal Form III is obtained and when no methanol is present and only toluene is used as the sole solvent, Crystal Form IV is obtained.
  • Crystal Form III shows moderate peaks at 7.0 and 14.0 and weak peaks at 3.5, 8.7, 9.4, 10.1 , 10.5, 11.1, 16.5, 17.6, 18.1, 19.6, 21.1 and 25.7, and Crystal Form IV shows a strong peak at 6.3, a moderate peak at 15.8 and weak peaks at 8.7, 9.5, 9.9 and 16.5.
  • Crystal Form V is obtained.
  • Crystal Form V shows a strong peak at 6.8, a moderate peak at 13.6 and broad weak peaks at 3.6, 9.2, 10.7 and 19.5.
  • chlorinated solvents may not be advantageous for environmental or other reasons, the crystal forms obtainable by processes employing chlorinated solvents show advantage in ease of filtration as the crystal habit is prismatic (thick needle).
  • Crystal Forms I, Il and V are solvates.
  • Crystal Form Il on heating becomes Crystal Form Vl.
  • Crystal Form Vl shows moderate peaks at 6.8 and 8.8 and broad weak peaks at 5.6, 8.1, 14.3, 17.6 and 19.0.
  • the solubility of BOC-protected 2R.3S-N- isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl) ⁇ p-nitrpbenzene-sulfonylamide in propan-1 - ol is less than 3%w/w at 6O 0 C.
  • the solubility of BOC-protected 2R,3S-N-isobutyl-N-(2- hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene-sulfonylamide in ethanol is better than that in C 3 and C 4 -alcohols, but is still lower than the solubility in methanol. Crystals obtained from ethanol are thinner and smaller needle crystals (acicular as opposed to prismatic) and therefore would prove inferior to methanol from a processing perspective. Similarly, acetone and 2-pentanone yield small acicular crystals.
  • the BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p- nitrobenzene-sulfonylamide employed in the first and further aspects of the present invention may be obtained by any method known in the art.
  • the BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene-sulfonylamide is prepared from a BOC-protected epoxide of Formula (1) or a halomethylalcoho! of Formula (2).
  • Example 1 Preparation of BOC-protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-ammo-4- phenylbutyl)-p-nitrobenzene-sulfonylamide.
  • the solid was then isolated by filtration and washed with 10% v/v ethyl acetate/methanol (3 x 144g).
  • the isolated crystals are prismatic (thick needle) and thus are amenabie to easy filtration.
  • Scanning Electron Microscopy shows 'fluted' rod shaped particles that are up to ⁇ 200.0 micron long.
  • XRD analysis (Siemens D5000 X-Ray Diffractometer, 2 ⁇ , CuKa radiation) shows the crystals to be Crystal Form Il with strong peaks at 5.3 and 8.3, moderate peaks at 6.7, 10.7, 13.4, 18.8, 19.6, 21.3 and 23.8 and weak peaks at 7.9, 17.3, 20.6 and 21.9.
  • Example 2 Genera! Method: Preparation of the different crystalline forms of BC 1 C- protected 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzene- sulfonylamide by equilibration in solvent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Un procédé de préparation de certains intermédiaires de sulfonamide utilisés dans la préparation d'inhibiteurs de VIH et leurs formes cristallines.
PCT/GB2006/002140 2005-06-10 2006-06-12 Procede et compose Ceased WO2006131757A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US11/917,090 US20080200724A1 (en) 2005-06-10 2006-06-12 Process and Compound
JP2008515294A JP2009502741A (ja) 2005-06-10 2006-06-12 調製方法と化合物
CA002608511A CA2608511A1 (fr) 2005-06-10 2006-06-12 Procede et compose
EP06744186A EP1893565A1 (fr) 2005-06-10 2006-06-12 Procede et compose

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0511807.0 2005-06-10
GBGB0511807.0A GB0511807D0 (en) 2005-06-10 2005-06-10 Process and compound

Publications (1)

Publication Number Publication Date
WO2006131757A1 true WO2006131757A1 (fr) 2006-12-14

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PCT/GB2006/002140 Ceased WO2006131757A1 (fr) 2005-06-10 2006-06-12 Procede et compose

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US (1) US20080200724A1 (fr)
EP (1) EP1893565A1 (fr)
JP (1) JP2009502741A (fr)
CN (1) CN101193857A (fr)
CA (1) CA2608511A1 (fr)
GB (1) GB0511807D0 (fr)
WO (1) WO2006131757A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114685327A (zh) * 2020-12-30 2022-07-01 重庆博腾制药科技股份有限公司 一种抗hiv类药物中间体晶型及其制备方法
CN118026896A (zh) * 2020-12-30 2024-05-14 上海飞腾医药科技有限公司 抗hiv类药物中间体晶体的生长方法和所得晶体
CN114685326A (zh) * 2020-12-30 2022-07-01 重庆博腾制药科技股份有限公司 抗hiv类药物中间体新晶型及其制备方法
CN114685324A (zh) * 2020-12-30 2022-07-01 重庆博腾制药科技股份有限公司 抗hiv类药物中间体晶型及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0774553A1 (fr) * 1995-11-07 1997-05-21 Gebroeders Kooy B.V. Couverture de toit

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0774553A1 (fr) * 1995-11-07 1997-05-21 Gebroeders Kooy B.V. Couverture de toit

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BEAULIEU, ANDERSON, CAMERON, CROTEAU, GORYS, GRAND-MAÎTRE, LAMARRE, LIARD, PARIS, PLAMONDON, SOUCY, THIBEAULT, WERNIC, YOAKIM: "2',6'-Dimethylphenoxyacetyl: A new achiral high affinity P3-P2 ligand for peptidomimetic-based HIV protease inhibitors.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 43, 2000, pages 1094 - 1108, XP002396633 *

Also Published As

Publication number Publication date
CN101193857A (zh) 2008-06-04
CA2608511A1 (fr) 2006-12-14
US20080200724A1 (en) 2008-08-21
JP2009502741A (ja) 2009-01-29
GB0511807D0 (en) 2005-07-20
EP1893565A1 (fr) 2008-03-05

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